Tuberculosis (TB) and Acquired Immune Deficiency Syndrome (AIDS), together, lead to the death of more than four million people annually, world-wide. The public health system in third world faces unmitigated disaster due to the twin assault from these pandemics. The emergence of Multi Drug-Resistant (MDR) and Extensively Drug-Resistant (XDR) strains of Mycobacterium tuberculosis (Mtb), the failure of Bacille Calmette- Guerin (BCG) vaccine to control the spread of TB, and our inability to develop effective anti-TB drugs has worsened this situation. Human Immune Virus (HIV)-induced immuno-suppression is a substantial contributor to TB reactivation;perhaps one-quarter of all HIV cases go on to develop active TB. The world-wide AIDS situation is equally gloomy. The frontline candidate vaccines against AIDS have failed in clinical trials. We still do not completely understand mechanisms of AIDS pathogenesis and correlates of protection. Even the advent of Anti-retroviral therapy (ART) has not been able to impact this situation. New drugs and vaccines are urgently needed to combat both the TB and AIDS. Robust animal models of TB, AIDS and TB-AIDS co- infection will be a crucial part of the strategy to develop and test vaccines and drugs against these diseases. It has been possible to model AIDS extremely well in rhesus macaques infected with Simian immune Virus (SIV). These macaques undergo a rapid decline in the CD4+ T cell levels in peripheral blood and various lymphoid tissues following infection, and develop chronic to acute AIDS characterized by severe immune deficiency. Infection of macaques with Mtb produces a variety of outcomes, including primary fulminate TB, chronic, slowly progressive TB, or latent infection, thus accurately recapitulating the host-driven diversity of human TB. We have recently demonstrated the capability to infect rhesus macaques with a high- or low-dose of aerosolized Mtb, producing active pulmonary TB and latent disease, respectively. The ability to infect macaques with Mtb via the aerosol route will allow us to model TB as closely as possible to natural disease. In this proposal, we would like to combine our recently developed aerosol-based model of TB in rhesus macaques, to the previously existing SIV infection model in the same species, in order to study the clinical, immunological, molecular and pathological parameters of co-infection between SIV and Mtb. Consequently, the proposal aims to achieve the following research objectives: 1. Establish a model of M. tuberculosis/SIV co- infection in rhesus macaques, mimicking the natural route of infection for both pathogens. 2. Determine if rhesus macaques latently infected with low-dose aerosols of M. tuberculosis reactivate to active disease in significantly different fashion, following intravenous infection with SIV. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) and Acquired Immune Deficiency syndrome (AIDS) are two of the most devastating infectious diseases of mankind, together resulting in close to four million annual deaths. The crisis has further worsened due to a collapse of public health system in many nations, the apparent synergy between AIDS and TB, the spectacular failure of BCG (the anti-TB vaccine) and AIDS vaccines in the pipeline, and drug resistance. AIDS is caused by Human Immunodeficiency Virus (HIV), while TB is caused by Mycobacterium tuberculosis (Mtb). Rhesus macaques infected with Simian Immunodeficiency Virus (SIV) are an accurate model of human AIDS. This model has been instrumental in developing our current understanding of AIDS pathogenesis and pathology. There is also a renewed interest in the nonhuman primate model of TB. These animals accurately model various phases of clinical TB, and portray the entire spectrum of the pathology of human TB. We recently exposed rhesus macaques to high dose of M. tuberculosis aerosols. This led to the development of significant pulmonary TB. Exposure of rhesus macaques to a low dose of Mtb aerosols on the other hand, led to latent infection. We believe that the ability to infect NHP's with infectious aerosols of Mtb represents a significant advance, since it allows us to study the disease in a natural context. Consequently, the proposal aims to achieve the following research objectives: 1. Establish a model of Mtb/SIV co-infection in rhesus macaques, mimicking the natural route of infection for both pathogens. 2. Determine if rhesus macaques latently infected with low-dose aerosols of Mtb reactivate to active disease in a significantly different fashion, following intravenous SIV infection.